Project Summary A large percentage of drug candidates fail at the clinical trial stage due to a lack of efficacy and unacceptable toxicity, primarily because the commonly used preclinical models (in vitro cell cultures and in vivo animal models) provide limited information about how a drug will affect human physiology. The need for more physiologically relevant in vitro systems for preclinical efficacy and toxicity testing has led to a major effort to develop ?Microphysiological Systems (MPS)? or ?Tissue Chips (TC)? based on engineered human tissue constructs. The TC development process requires an initial assessment of viability and functionality, followed by an examination of the TC response to various stimuli, including drugs, toxins, and disease-related cues. These extensive development efforts take place mainly in the developer?s lab, and the reproducibility of the TC results are rarely assessed by an independent research group or transferred to industry partners for use in drug development. Although there is a need for more physiologically-relevant preclinical testing technologies, the transition of TC technologies from developer lab to industry remains challenging. Successful transfer and deployment of TC technologies requires systematic characterization and validation of the systems, preferably by an independent external testing facility. Therefore, we propose to continue filling this gap between tissue chip developers and industrial application of TC technologies with our Translational Center of Tissue Chip Technologies (TC2T), which will continue to provide unbiased testing and validation of MPS technologies as reflected in the current RFA. TC2T takes a holistic and mechanistic approach?based on quantitative systems pharmacology (QSP)? that combines quantitative experimental biology, computational biology, and biostatistics to characterize these complex systems and translation of experimental insights to clinical insights. Our TC2T team at MIT includes tissue engineers, experimentalists, and computational biologists and serves as the core of the testing center. This multidisciplinary team is highly experienced in TC technology testing and will be responsible for model- guided experimental design, experimental execution, data acquisition in collaboration with partner sites, data analysis, and reporting. TC2T will lead to transparent and unbiased TC testing to ensure adoption of well- characterized and independently validated TC platforms by the pharmaceutical industry to use in drug development and toxicology testing and government agencies to use in the regulatory decision-making process.